The major cause of death from squamous cell cancer of the head and neck (SCCHN) is progressive growth with invasion and metastasis. The design of effective new therapies against SCCHN requires a better understanding of the process of metastasis. Recent data show that the progressive growth and metastasis of SCCHN are dependent on the development of new vasculature, i.e., angiogenesis. We hypothesize that the angiogenesis and hence aggressive nature of human SCCHN is due to an imbalance between proangiogenic (IL-8, bFGF, VEGF, MMP-9) and antiangiogenic (IFN-alpha/-beta) molecules; restoration of this balance by systemic administration of an optimal dose of IFN is expected to inhibit angiogenesis and, therefore, progression and metastasis of human SCCHN. IFN-alpha and -beta negatively regulate the activity of NF-kB family transcription factors. The absence of IFN-beta (in the tumor and surrounding tissues) leads to enhanced activity of NF-kB and hence enhanced expression of IL-8 and MMP-9 along with increased angiogenesis. Restoration of IFN-alpha should therefore inhibit angiogenesis and, hence, progression of SCCHN. We shall determine whether increased microvessel density and elevated expression of bFGF, IL-8, VEGF, MMP-9, and reduced expression of IFN are found in surgical specimens of human SCCHN from patients with more advanced disease or poorer treatment outcomes. We also will use a relevant orthotopic (tongue implantation) nude mouse model to determine if metastatic cell line variants in this model demonstrate NF-kB activation, and/or elevated expression of bFGF, IL-8, VEGF, MMP-9, and reduced expression of IFN. Since neoplastic angiogenesis is associated with a decrease in tissue level of IFN (alpha and beta), we will determine if systemic administration of an optimal dose of IFN can inhibit angiogenesis of human SCCHN implanted orthotopically in nude mice. Finally, we will evaluate the antiangiogenic activity of pegylated IFN in the preoperative setting for patients with SCCHN. Information gained through these studies will contribute to our understanding of angiogenesis in human SCCHN as it relates to invasion and metastasis on the systemic, cellular, and molecular levels; this is essential for the design of effective anti-angiogenic therapy and rapid translation to the clinic for the benefit of patients.